Next Steps in Bladder Cancer to Include Combination Immunotherapy

Andrea Necchi, MD

While the 5 PD-1/PD-L1 inhibitors approved by the FDA in a 2-year span have drastically shifted the therapeutic paradigm of bladder cancer, researchers are already taking the next steps that include combination regimens to have a greater benefit across patient subgroups, according to Andrea Necchi, MD.

The class of agents indicated for the second-line setting includes pembrolizumab (Keytruda), nivolumab (Opdivo), atezolizumab (Tecentriq), durvalumab (Imfinzi), and avelumab (Bavencio), yet pembrolizumab remains the sole checkpoint inhibitor to demonstrate an improvement in overall survival (OS) in a phase III study. Each of these inhibitors also elicit responses in approximately 15% to 25% of patients across differing populations.

To take the next step in this research, investigators are now combining immunotherapies together, or with chemotherapy, to create added benefits and more durable, long-lasting responses.

OncLive: Please provide an overview of your lecture at the 2017 EMUC Congress.

In an interview with OncLive during the 2017 EMUC Congress, Necchi, a medical oncologist at the Fondazione IRCCS Istituto Nazionale dei Tumori in Milan, Italy, discussed the evolution of bladder cancer therapies, the challenge with the currently available agents, and the next steps and clinical trials being conducted in the field.Necchi: I was asked to summarize the revolution of bladder cancer treatment in the advent of immune checkpoint inhibitors. It’s quite an issue because we have achieved multiple results from multiple trials, including the different populations.

The most important message may come from the major clinical trials that have been published in the last year. We have 2 different populations: those who have already received chemotherapy or the first-line, platinum-untreated patients. For the platinum-untreated patients, we had the results of 2 single-agent, single-arm trials with atezolizumab and with pembrolizumab. They were very similar—almost identical—in their design and endpoints, but not identical in the patient population that were included.

Basically, KEYNOTE-052 with pembrolizumab and cohort 1 of IMvigor 210 with atezolizumab led to the same results, meaning there were about 15% to 20% of patients who maintained a long-term response. These are patients benefitting from long-term immunotherapy and may avoid receiving chemotherapy in the long run. In this respect, these 2 trials led to, basically, very similar outcomes.

The other point is related to the population of patients who already received platinum-based chemotherapy. In this context, we have multiple phase II and some phase III trials [read out]. We have pembrolizumab from KEYNOTE-045, whereby pembrolizumab was compared with chemotherapy and showed the level 1 evidence of an improvement in survival compared with chemotherapy in these patients.

We have another phase III study with atezolizumab compared with chemotherapy, which failed to achieve the primary endpoint of OS for PD-L1—positive patients. It was positive for the intent-to-treat, not primary, population. The most important message from both trials…is that we have the possibility for these patients to respond to immunotherapy. The responses are in the range of 20% to 25% in this context. However, if a patient responds, they have a very high chance to maintain long-term response. In this respect, results from IMvigor 211 and KEYNOTE-045 are quite similar. This is the reason why both agents have been granted approval by the FDA and EMA.

Then, we have other phase II single-agent studies, including nivolumab in CheckMate-275, avelumab, and durvalumab. [These] are very close to the results of pembrolizumab and atezolizumab, with some conflicting signals regarding PD-L1 expression. These compounds are now FDA approved; only one of these other compounds, nivolumab, is granted EMA approval.

It is clear that one of the most important points now is patient selection. At the same time, [we know] that patient selection cannot rely on the role of PD-L1 by immunohistochemistry (IHC) because we don’t have signals supporting the role of predictive PD-L1 expression.

However, we have something else—the results from a translational study, mainly from IMvigor 210 mainly atezolizumab, that are supporting the role of other possible biomarkers. A clear biomarker seems to be the presence of inflamed microenvironment in the tumor, meaning the presence of activating T cells in the microenvironment, which clearly is linked to response and clinical benefit to checkpoint inhibitors.

The other point has to do with…the population of patients who harbor luminal tumors. Patients who are usually less likely to respond to immunotherapy [may harbor] FGFR alterations. FGFR is another target of another class of agents, pan-FGFR receptors, that are coming into the ground of bladder cancer treatment. The results of these trials would be presented in the first quarter of [2018]. The biology behind the possible association between FGFR alteration and poor response to PD-1/PD-L1 inhibitors strongly supports the possible use of this class of agents prior to or following the use of immune checkpoint inhibitors. We are now almost able to shape patients’ journeys, which seems to be worldwide, in order to identify possible druggable targets to be used prior to immunotherapy, or following progression on immunotherapy.

What has been the impact of PD-1 inhibition in bladder cancer?

There is still a role for old chemotherapy. There is still undoubtedly a role for cisplatin-based chemotherapy. Then, there is a possible role for chemotherapy after disease progression on checkpoint inhibitors. We have seen augmented activity of chemotherapy after prior exposure to checkpoint inhibitors; they are very small numbers but it seems chemotherapy may still have a role after the use of checkpoint inhibitors.The impact may be perceived and may be discussed on multiple perspectives. I would say, first, the most important impact has to do with the patient perspectives. For the first time, in this disease, we can hear the voice of patient advocates in bladder cancer—in Europe mainly.

Does having a phase III improvement in OS sway doctors toward treatment with pembrolizumab?

What is the importance of PD-L1 testing?

Since then, we have achieved important steps forward together with patients in Europe and we are trying to create a community of patients in Europe. The next step would be to try to better use these options in additional medical needs; for example, the issue of bladder preservation to not only cure advanced disease, but to preserve the disease in early stages. The use of immune checkpoint inhibitors may be regarded as a hope for patients, in order to have a better understanding of the way we can spare their bladder.Yes, not only from a regulatory viewpoint, but from the investigator and clinician viewpoint. We are handling data that may come from multiple trials, but most of the data are coming clearly from pembrolizumab. At the same time, there were results achieved with nivolumab, atezolizumab, avelumab, and durvalumab that are quite close to those of pembrolizumab. But, conservatively, we should first look at pembrolizumab data and then all the other phase II data are coming down.There are no roles so far for PD-L1 testing. All of the drugs being granted registration by the FDA and EMA are not being granted based on the use of PD-L1 via IHC; they are for all comers, regardless of PD-L1 expression.

At the same time, the process of patient selection and the need for selecting patients is a priority because we cannot afford the contemporary use of 5 different very similar compounds in all comers. Therefore, investigators are clearly asked to [do their] best to identify criteria for patient selection.

Of course, one of the most important notions that we have coming and moving beyond the role of PD-L1 expression comes from the mutational burden, which seems to be linked to the activity of immune checkpoint inhibitors. Mismatch repair deficiency is also clearly linked to the activity of immune checkpoint inhibitors. The class of patients less likely to respond to checkpoint inhibitors should be the next targets for clinical evaluation. The point will be to try to translate all these notions into something that may be used effectively and in clinical practice. However, the issue of patient selection is a priority based on the availability of so many similar compounds.

I am very eager to start our phase II study. The phase II study, which will run first in Milan, [Italy], the PEANUT study, is combining pembrolizumab with nab-paclitaxel (Abraxane). Nab-paclitaxel has already shown in the second-line setting to be an active compound in bladder cancer. There is a randomized study that is comparing nab-paclitaxel with a taxane in Canada. Nab-paclitaxel is one of the most effective [chemotherapy agents] in the platinum-treated population. There is an issue with tolerability; of course, one of the endpoints will be to try to prolong PFS.

We know that with the use of pembrolizumab alone, as well as the other immune checkpoint inhibitors alone, we cannot improve PFS. This is another very interesting point regarding the primary endpoints of these studies.

What are the remaining challenges with immunotherapy in bladder cancer?

There is a myriad of combinations that are running in phase I, II, and III studies worldwide in bladder cancer. We are combining different agents—immune checkpoint inhibitors with other immune checkpoint inhibitors, immune checkpoint with antiangiogenic drugs, or immune checkpoint inhibitors with personalized medicine. That is huge platter of possibilities for patients. This is, of course, an advantage and positive situation for patients with bladder cancer today.The biggest challenge for immunotherapy in bladder cancer remains in the very early stages. For example, in Milan, we are running a phase II study with pembrolizumab—the PURE-01 study—which is recruiting very fast. It provides a short course of administration of pembrolizumab—3 courses—and then radical cystectomy in all comers. Results are awaited next year. There is another very similar study, which provides administration of 2 courses of atezolizumab prior to radical cystectomy. We can really achieve a very important step forward from the biologic viewpoint [with these studies].

We have 3 big adjuvant randomized studies; the results from these studies are awaited, and, finally, we have multiple studies with single-agent or combination immunotherapy in Bacillus Calmette-Guerin-refractory patients in nonmuscle-invasive patients. The advent of new checkpoint inhibitors in this area will provide us with opportunity to work more closely and to better reach the way we globally treat patients with bladder cancer.